title: The effect of SN-6, a novel sodium-calcium exchange inhibitor, on contractility and calcium handling in isolated failing rat ventricular myocytes.
abstract: OBJECTIVE
  Specific Na(+) /Ca(2+) exchanger (NCX) inhibition is a potential strategy to correct reduced contractility and depleted sarcoplasmic reticulum (SR) Ca(2+) content in heart failure (HF). SN-6, a benzyloxyphenyl derivative and proposed selective NCX inhibitor, could be used for this purpose. This study aimed to evaluate the effects of SN-6 on contractility and Ca(2+) handling in normal and failing rat cardiomyocytes.
  
  
  METHODS
  HF was induced in rats by coronary artery ligation. Left ventricular myocytes were isolated and superfused with increasing concentrations of SN-6.
  
  
  RESULTS
  Sarcomere shortening, induced by field-stimulation, was reduced in amplitude with increasing concentrations of SN-6 compared with control solution. This effect was greater in failing cells. Kinetics of contractility (time to 90% peak and time to 50% relaxation) were significantly faster. Despite this, intracellular Ca(2+) transients demonstrated no change in the peak amplitude at low concentrations of SN-6, suggesting that SN-6 may affect myofilament sensitivity to Ca(2+) . Ten micro molar SN-6 significantly reduced peak Ca(2+) amplitude by 61.57% and 64.73% in normal and failing cells, respectively. Diastolic Ca(2+) was significantly increased at 1 μM SN-6. SR Ca(2+) content, assessed by rapid application of caffeine, was reduced in failing cells with 1 μM SN-6. Peak ICa , measured by whole-cell patch clamping, was significantly reduced in normal and failing myocytes at 1 μM SN-6.
  
  
  CONCLUSIONS
  Our data suggest that SN-6 is not a selective inhibitor of NCX and impairs contractility and Ca(2+) handling. Its use, together with similar putative NCX blockers, in correcting the contractile abnormalities of heart failure requires further studies.
authors.affiliation: Cell Electrophysiology, Heart Science Centre, NHLI, Imperial College London, London, UK.
authors.forename: Ajay
authors.initials: A
authors.lastname: Gandhi
authors.forename: Urszula
authors.initials: U
authors.lastname: Siedlecka
authors.forename: Adarsh P
authors.initials: AP
authors.lastname: Shah
authors.forename: Manoraj
authors.initials: M
authors.lastname: Navaratnarajah
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: Cesare M
authors.initials: CM
authors.lastname: Terracciano
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D006333:Heart Failure / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; D001593:Benzyl Compounds; D019831:Sodium-Calcium Exchanger; D053778:Thiazolidines; D002118:Calcium
keywords: Benzyloxyphenyl; Calcium handling; Contractility; Heart failure; Myofilament sensitivity; NCX; Rat cardiomyocyte; SN-6; Sodium-calcium exchanger